The hypothesis that the accumulation of genetic or epigenetic events leads to cancer will be tested using albumin and alphafetoprotein (AFP) gene promoter/oncogene hybrids in transgenic mice through five specific aims: 1) Construction, and in vitro testing of hybrid genes containing the albumin promoter controlling a mutant p53 gene or wild type p53 gene, and hybrid genes containing the AFP regulatory region joined to the SV40 large tumor antigen (TAg) or human c-Ha-ras (the T24 transforming oncogene). 2) Establishment of transgenic lines expressing different levels of the oncogene products. The expression of the genes and the development of liver lesions with age will be systematically examined and compared to non-transgenic littermates; 3) Depending on the production of tumors in these transgenic strains, cross breeding will be done to induce inhibition of tumor development in lines that develop tumors and to produce tumors in lines that do not. 4) Evaluation of the effect of non-carcinogenic events that produce liver cell proliferation and activation of the AFP promoter/oncogene construct in adults of the transgenic crossings that do not produce tumors. 5) Determination of the effect of reactivation of AFP promoter controlled genes by chemical hepatocarcinogens on expression of the transgene and development of hepatocellular carcinomas in mice that are resistant to tumor development. The results should not only test the hypothesis of Vogelstein of the role of accumulated genetic and epigenetic events in the development of tumors, but also test the hypothesis of. developmental control of "proto" oncogenes